The present invention relates to novel substituted 1,3-oxathiolane compounds having pharmacological activity, to pharmaceutical compositions containing them, and to the use of these compounds in the antiviral treatment of mammals.
Retroviral infections are a serious cause of disease, most notably, the acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus (HIV) has been recognized as the etiologic agent of AIDS. Compounds having an inhibitory effect on HIV multiplication or otherwise effective in the therapy of retroviral infections are being actively sought.
H. Mitsuya et al., xe2x80x9c3xe2x80x2-Azido-3xe2x80x2-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitroxe2x80x9d, Proc. Natl. Acad. Sci. USA, 82, pp. 7096-7100 (1985), refers to 3xe2x80x2-azido-3xe2x80x2-deoxythymidine of formula (A), commonly referred to as AZT. This compound is said to be useful in providing some protection for AIDS carriers against the cytopathogenic effect of immunodeficiency virus (HIV). 
H. Mitsuya and S. Broder, xe2x80x9cInhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2xe2x80x2,3xe2x80x2-dideoxynucleosidesxe2x80x9d, Proc. Natl. Acad. Sci. USA, 83, pp. 1911-15 (1986), have also referred to a group of 2xe2x80x2,3xe2x80x2-dideoxynucleosides shown in formula (B) which are said to possess protective activity against HIV-induced cytopathogenicity. 
P. Herdewijn et al., xe2x80x9c3xe2x80x2-Substituted 2xe2x80x2,3xe2x80x2-dideoxynucleoside analogues as potential anti-HIV(HTLV-III/LAV) agentsxe2x80x9d, J. Med. Chem., 30, pp. 1270-1278 (1987), describe the anti-HIV activity of a series of 3xe2x80x2-substituted nucleoside analogues. While 3xe2x80x2-fluoro analogues of 3xe2x80x2-deoxythymidine and 2xe2x80x2,3xe2x80x2-dideoxy-cytidine shown in formulas (C) and (D) are found to possess potent antiretroviral activity, substituents linked to the 3xe2x80x2-carbon via a thio or oxygen bridge did not yield active products. 
Analysis of molecular conformation studies in P. Van Roey et al., xe2x80x9cCorrelation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virusxe2x80x9d, Proc. Natl. Acad. Sci. USA, 86(10), pp. 3929-3933 (1989), indicate that active anti-HIV nucleoside analogues have 3xe2x80x2 carbon conformations on the side opposite to the base.
D. Huryn et al., xe2x80x9cSynthesis of iso-ddA, member of a novel class of anti-HIV agentsxe2x80x9d, Tetrahedron Lett., 30(46), pp. 6259-6262 (1989), refer to the iso-nucleoside analogue of formula (E) as a stable inhibitor of HIV replication. 
R. Vince and M. Hua, xe2x80x9cSynthesis and anti-HIV activity of carbocyclic 2xe2x80x2,3xe2x80x2-didehydro-2xe2x80x2,3xe2x80x2-dideoxy 2,6-disubstituted purine nucleosidesxe2x80x9d, J. Med. Chem., 33(1), pp. 17-21 (1990), describe the analogues shown in formulas (F) and (G) as having anti-HIV activity. The unsaturated analogue (F) shows greater selectivity and potency as an inhibitor of HIV replication than the saturated analog (G). 
C. Chu et al., xe2x80x9cSynthesis and structure-activity relationships of 6-substituted 2xe2x80x2,3xe2x80x2-dideoxypurine nucleosides as potential anti-human immunodeficiency virus agentsxe2x80x9d, J. Med. Chem., 33(6), pp. 1553-1561 (1990), describe the N6-methyl derivative shown in formula (H) as having greater potency against HIV than unmethylated 2xe2x80x2,3xe2x80x2-dideoxyadenosine. 
Finally, B. Belleau et al., xe2x80x9cDesign and activity of a novel class of nucleoside analogues effective against HIV-1xe2x80x9d, Abstracts of papers, Fifth International Conference on AIDS, Montreal, T.C.O. 1, p. 515 (1989), refer to dioxolanes and oxathiolanes of formulas (J) and (K) as having potent anti-HIV activity. 
The cis isomer of formula (K) has been found to be active against HIV and HBV, and its unnatural enantiomer ((2R, 5S cis) referred to as xe2x80x9cthe (xe2x88x92) enantiomerxe2x80x9d has been found to have surprisingly low toxicity. Now named lamivudine or xe2x80x9c3TC(trademark)xe2x80x9d, this new anti-viral drug is becoming the treatment of choice for combination therapy of AIDS patients and for sole therapy for HBV patients.
Although lamivudine (3TC(trademark)) has been found to be an extremely interesting compound in the clinic, there is always the possibility that the patient develops virus strains that are resistant to it after prolonged periods of treatment. There is therefore, still a need to develop anti-viral agents that are active against nucleoside-resistant viral strains, in particular, against 3TC(trademark)-resistant viral strains.
Classes of compounds known as 2-substituted 4-substituted 1,3-oxathiolanes have been found to have potent antiviral activity. In particular, these compounds have been found to act as potent inhibitors of HIV-1 replication in T-lymphocytes over a prolonged period of time with less cytotoxic side effects than compounds known in the art. These compounds have also been found active against 3TC-resistant HIV strains. These compounds are also useful in prophylaxis and treatment of hepatitis B virus infections.
There are accordingly provided in a first aspect of this invention a single enantiomer of compounds of formula (I) in the cis configuration: 
wherein R1 is hydrogen,
R2 is cytosine or 5-fluorocytosine, and pharmaceutically acceptable salts and esters thereof.
As used herein, xe2x80x9ca pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an antivirally active metabolite or residue thereof.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, p-toluene sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94(C1-4 alkyl)4+ salts.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable salts and esters thereof, at functional groups in both the cytosine moiety, and at the hydroxymethyl group of the oxathiolane ring. Modification at all such functional groups is included within the scope of the invention. However, of particular interest are pharmaceutically acceptable salts and esters (e.g., esters or esters of amino acids) obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
Preferred esters of the compounds of formula (I) include the compounds in which R1 is replaced by a carboxyl function Rxe2x80x94(CO) in which the non-carbonyl moiety R of the ester grouping is selected from hydrogen, straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl optionally substituted by halogen, C1-4 alkyl or C1-4 alkoxy); substituted dihydro pyridinyl (e.g., N-methyldihydro pyridinyl); sulphonate esters such as alkyl- or aralkylsulphonyl (e.g., methanesulphonyl); sulfate esters; amino acid esters (e.g., L-valyl or L-isoleucyl) and mono, di- or triphosphate esters.
Also included within the scope of such esters are esters derived from polyfunctional acids such as carboxylic acids containing more than one carboxyl group, for example, dicarboxylic acids HO2C(CH2)nCO2H where n is an integer of 1 to 10 (for example, succinic acid) or phosphoric acids. Methods for preparing such esters are well known. See, for example, E. Hahn et al., xe2x80x9cNucleotide dimers as anti-human immunodeficiency virus agentsxe2x80x9d, Nucleotide Analogues As Antiviral Agents, J. C. Martin, Ed. Symposium Series #401, American Chemical Society, pp. 156-159 (1989) and M. Busso et al., xe2x80x9cNucleotide dimers suppress HIV expression in vitroxe2x80x9d, AIDS Research and Human Retroviruses, 4(6), pp. 449-455 (1988).
Specific compounds of formula (I) include:
Compound #1: 
2R-hydroxymethyl-4R-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane;
compound #2: 
2S-hydroxymethyl-4S-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane;
compound #3: 
2R-hydroxymethyl-4R-(5xe2x80x2-fluorocytosin-1xe2x80x2-yl)-1,3-oxathiolane; and
compound #4
2S-hydroxymethyl-4S-(5xe2x80x2-fluorocytosin-1xe2x80x2-yl)-1,3-oxathiolane;
and pharmaceutically acceptable salts and esters thereof.
In the processes for preparing the compounds of this invention, the following definitions are used:
R2 is cytosine or 5-fluorocytosine;
Rw is hydrogen, trisubstituted silyl, C1-6 alkyl, aralkyl such as benzyl or trityl, C1-16 acyl, preferably a benzoyl or a benzoyl substituted in any position by at least one halogen (bromine, chlorine, fluorine or iodine), C1-6 alkyl, C1-6 alkoxy, nitro, or trifluoromethyl group;
Rx is C1-6 alkyl; and
L is a xe2x80x9cleaving groupxe2x80x9d, i.e., an atom or group which is displaceable upon reaction with an appropriate base, with or without a Lewis acid. Suitable leaving groups include acyloxy groups, alkoxy groups, e.g., alkoxy carbonyl groups such as ethoxy carbonyl; halogens such as iodine, bromine, chlorine, or fluorine; amido; azido; isocyanato; substituted or unsubstituted, saturated or unsaturated thiolates, such as thiomethyl or thiophenyl; substituted or unsubstituted, saturated or unsaturated seleno or selenino compounds, such as phenyl selenide or alkyl selenide; and substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic ketones such as methyl ketone.
A suitable leaving group may also be xe2x80x94OR, where R is a substituted or unsubstituted, saturated or unsaturated alkyl group, e.g., C1-6 alkyl or alkenyl group; a substituted or unsubstituted aliphatic or aromatic acyl group, e.g., a C1-6 aliphatic acyl group such as acetyl and an aromatic acyl group such as benzoyl; a substituted or unsubstituted, saturated or unsaturated alkoxy or aryloxy carbonyl group, such as methyl carbonate and phenyl carbonate; substituted or unsubstituted sulphonyl imidazolide; substituted or unsubstituted aliphatic or aromatic amino carbonyl group, such as phenyl carbamate; substituted or unsubstituted alkyl imidate group such as trichloroacetamidate; substituted or unsubstituted, saturated or unsaturated phosphonates, such as diethylphosphonate; substituted or unsubstituted aliphatic or aromatic sulphonyl group, such as tosylate; or hydrogen.
Oxathiolane compounds of formula (I), 
and pharmaceutically acceptable, salts and esters, may be prepared according to the processes discussed herein or by any method known in the art for the preparation of compounds of analogous structure. The compound of this invention can be produced by the methods described by Mansour et al., xe2x80x9cAnti-Human Immunodeficiency Virus and Anti-Hepatitis-B Virus Activities and Toxicities of the Enantiomers of 2xe2x80x2-Deoxy-3xe2x80x2-oxa-4xe2x80x2-thiacytidine and Their 5-Fluoro Analogues in vitroxe2x80x9d, J. Med. Chem., 1995, Vol. 38, No. 1, pp. 1-4, which is incorporated herein by reference.
In one such process for producing oxathiolanes of this invention, a compound of formula (V), 
wherein Rw is hydrogen or a hydroxyl protecting group and L is a displaceable atom or group, i.e., a leaving group, is reacted with an appropriate base.
In a second process for producing oxathiolanes of this invention, a compound of formula (VI) 
may be converted to a compound of formula (I) by conversion of the anomeric NH2 group to the required base by methods well known in the art of nucleoside chemistry.
The 1,3-oxathiolanes of formula (I) may also be prepared, for example, by reaction of an aldehyde of formula (VII)
C6H5COOCH2CHOxe2x80x83xe2x80x83(VII)
with 2-mercaptoethanol in a compatible organic solvent followed by Pummerer rearrangements as is known in the art (T. Durst, xe2x80x9cDimethylsulfoxide in Organic Synthesisxe2x80x9d, Adv. Org. Chem., E. C. Taylor and B. Wynberg, Eds., 6, pp. 356-365 (1969)) to give 1,3-oxathiolanes of formula (V), which are converted to 1,3-oxathiolanes of formula (I) by methods known in the art of nucleoside chemistry.
Another process for preparing the 1,3-oxathiolanes of formula (I) is illustrated in SCHEME 1.
The various steps involved in the synthesis of 1,3-oxathiolanes of formula (I) as illustrated in SCHEME 1 may be briefly described as follows: 
Step 1: Benzoyloxyacetaldehyde of formula (VII) or any aldehyde of the formula RwOCH2CHO (C. D. Hurd and E. M. Filiachione, xe2x80x9cA new approach to the syntheses of aldehyde sugarsxe2x80x9d, J. Am. Chem. Soc., 61, pp. 1156-1159 (1939)) is condensed with a mercaptoalcohol such as 2-mercaptoethanol in a compatible organic solvent, such as toluene, containing a catalytic amount of a strong acid to give the intermediate shown in formula (VIII).
Step 2; The 1,3-oxathiolane of formula (VIII) is then oxidized with a peracid such as magnesium monoperoxyphthalic acid in a compatible organic solvent such as methylene chloride containing a salt such as tetrabutyl ammonium bromide to give the sulfoxide intermediate shown in formula (IX).
Step 3: The sulfoxide intermediate shown in formula (IX) is treated with an acid anhydride such as acetic anhydride or any other anhydride of the formula (RXCO)2O in the presence of a buffer such as tetra-n-butylammonium acetate to give the 2,4-disubstituted-1,3-oxathiolane of formula (X) (T. Durst, Adv. Org. Chem., 6, pp. 356-365 (1969)).
Step 4: The 1,3-oxathiolane of formula (X) is then reacted with a pyrimidine base or analogue thereof, (e.g., cytosine) previously silylated with, for example, hexamethyldisilazane in a compatible solvent using a Lewis acid or trimethylsilyl triflate to give the intermediate of formula (XI) as cis and trans isomers. The isomers may be separated, preferably by chromatography, to give pure cis (XI) and pure trans (XI).
Step 5: The benzoate function of the compound of formula (XI) (cis or trans isomer), is hydrolyzed using a base such as methanolic ammonia to obtain the compound shown in formula (XII) as cis- or trans-isomer. preferably under pressure, to give the product shown in Many of the reactions in the above-described processes have been extensively reported in the context of pyrimidine nucleoside synthesis, for example, in L. B. Townsend, xe2x80x9cSynthesis and reaction of pyrimidine nucleosidexe2x80x9d, Chemistry of Nucleoside and Nucleotides vol. 1, Eds., Plenum Press, New York (1989) at pages 1-95, the text of which is incorporated by reference herein.
In the above-described process, the compounds of formula (I) are generally obtained as a mixture of the cis and trans isomers.
The cis and trans isomers may be separated, for example, by acetylation, e.g., with acetic anhydride followed by separation by physical means, e.g., chromatography on silica gel and deacetylation, e.g., with methanolic ammonia or by fractional crystallization.
Resolution of the final product, or an intermediate or starting material therefore may be effected by any suitable method known in the art: see for example, Stereochemistry of Carbon Compounds, by E. L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents, by S. H. Wilen.
Where the compound of formula (I) is desired as a single enantiomer it may be obtained either by resolution of the mixture of the two cis enantiomers (by chiral HPLC) or by stereospecific synthesis from isometrically pure starting material or any convenient intermediate. Thus, the compound of formula (I) or any convenient intermediate may be obtained by chiral HPLC using a suitable stationary phase for example acetylated xcex2-cyclodextrin or cellulose triacetate and a suitable solvent for example an alcohol such as ethanol or an aqueous solution such as triethyl ammonioum acetate. Alternatively, the compound of formula (I) or any convenient intermediate may be resolved by enzyme mediated enatioselective catabolism with a suitable enzyme such as cytidine deaminase or selective enzymatic degradation of a suitable derivative using a 5xe2x80x2-nucleotidase for example see Storer et al., xe2x80x9cThe resolution and Absolute Stereochemistry of the Enantiomers of cis-1[2(Hydroxomethyl)-1,3-Oxathiolan-5-Yl)Cytosine (BCH-189): Equipotent Anti-HIV Agentsxe2x80x9d, Nucleosides and Nucleotides, 12(2), 225-236 (1993). When the resolution is effected enzymatically, the enzyme may be employed either in solution or in immobilized form. Enzymes in immobilized form are known in the art for example, by adsorption onto a resin such as Eupergit.
It will be appreciated that the reactions of the above-described processes may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g., benzyl), acyl or aryl (e.g., 2,4-dinitrophenyl); subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Ed. J. F. W. McOmie (Plenum Press, 1973) or xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene (John Wiley and Sons, 1981 which is incorporated by reference herein. Examples of suitable hydroxyl protecting groups include groups selected from alkyl (e.g., methyl, t-butyl or methoxymethyl), aralkyl (e.g., benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl, (e.g., acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g., t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl may similarly be removed by solvolysis, e.g., by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups so formed at an appropriate stage in the synthesis. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
Pharmaceutically acceptable salts of the compounds of the invention may be prepared as described in U.S. Pat. No. 4,383,114, the disclosure of which is incorporated by reference herein. Thus, for example, when it is desired to prepare an acid addition salt of a compound of formula (I), the product of any of the above procedures may be converted into a salt by treatment of the resulting free base with a suitable acid using conventional methods. Pharmaceutically acceptable acid addition salts may be prepared by reacting the free base with an appropriate acid optionally in the presence of a suitable solvent such as an ester (e.g., ethyl acetate) or an alcohol (e.g., methanol, ethanol or isopropanol). Inorganic basic salts may be prepared by reacting the free base with a suitable base such as an alkoxide (e.g., sodium methoxide) optionally in the presence of a solvent such as an alcohol (e.g., methanol). Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods.
A compound of formula (I) may be converted into a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as POCl3, or a suitable esterifying agent, such as an acid halide or anhydride, as appropriate. An ester or salt of a compound of formula (I) may be converted to the parent compound, for example, by hydrolysis.
The compounds of the invention possess anti-viral activity. In particular these compounds are effective in inhibiting the replication of hepatitis B virus and retroviruses, including human retroviruses such as human immunodeficiency viruses (HIV""s), the causative agents of AIDS.
There is thus provided as a further aspect of the invention a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use as an active therapeutic agent in particular as an antiviral agent, for example in the treatment of hepatitis B viral and retroviral infections such as HIV infection.
There is also provided in a further or alternative aspect of this invention, use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a viral infection.
Such viral infections may be, in particular HIV and HBV infections.
In a further or alternative aspect there is provided a method for the treatment of a viral infection, in particular an infection caused by hepatitis B virus or a retrovirus such as HIV, in a mammal, including man, comprising administration of an effective amount of an antiviral compound of formula (I) or a pharmaceutically acceptable derivative thereof.
The compounds of the invention are also useful in the treatment of AIDS-related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia), anti-HIV antibody-positive and HIV-positive conditions, Kaposi""s sarcoma, thrombocytopenia purpura and opportunistic infections.
The compounds of the invention are also useful in the prevention or progression to clinical illness of individuals who are anti-HIV antibody or HIV-antigen positive and in prophylaxis following exposure to HIV.
The compounds of formula (I) or the pharmaceutically acceptable salts and esters thereof, may also be used for the prevention of viral contamination of biological fluids such as blood or semen in vitro.
It will be appreciated by those skilled in the art that references herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
It will be further appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, a suitable dose will be in the range from about 1 to about 750 mg/kg of body weight per day, such as 3 to about 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to 75 xcexcM, preferably about 2 to 50 xcexcM, most preferably about 3 to about 30 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus containing about 0.1 to about 110 mg/kg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution; as a suspension; or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
The compounds according to the invention may also be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored based, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Pharmaceutically formulations suitable for rectal administration wherein the carrier is a solid, are most preferably represented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in molds.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, such carriers as are known in the art to be appropriate.
For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops.
Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.
For administration by inhalation, the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
When desired, the above described formulations adapted to give sustained release of the active ingredient, may be employed.
The pharmaceutical compositions according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.
The compounds of the invention may also be used in combination therapy to avoid the production of resistant viral strains.
In particular, the compounds of the invention may also be used in combination with other therapeutic agents, for example, other anti-infective agents. In particular the compounds of the invention may be employed together with known antiviral agents.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable derivative thereof together with another therapeutically active agent, in particular, an antiviral agent.
Suitable therapeutic agents for use in such combinations include nucleoside analogues such as 3TC(trademark), 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), 3xe2x80x2-deoxythymidine, 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine, and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir, ganciclovir, interferons such as alpha-, beta- and gamma-interferon; glucuronation inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, ampligen, thymomodulin, thymopentin, foscarnet, glycosylation inhibitors such as 2-deoxy-D-glucose, castanospermine, 1-deoxynojirimycin; and inhibitors of HIV binding to CD4 receptors such as soluble CD4, CD4 fragments, CD4-hybrid molecules and inhibitors of the HIV aspartyl protease such as L-735,524.
Suitable further therapeutic agents for use in such combinations also include non nucleoside reverse transcriptase inhibitors such as revirapine, TIBO, HEPT, BHAP, MKC-422, xcex1-APA, TSAO, calanolides, and L-697,661.
Preferably, the further therapeutic agent is selected from: 3TC(trademark), AZT, ddC, and ddI.
The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention.
When the compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may be either the same or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
It will be further appreciated that the amount of a compound of the invention and the amount of the further therapeutic agent required for use in treatment will vary not only with the particular compound of the invention and the further therapeutic agent selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, a suitable dose of the compound of the invention will be in the range from about 1 to about 750 mg/kg of body weight per day, such as 3 to about 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day. A suitable dose of the further therapeutic agent will be in the range from about 1 to about 750 mg/kg of body weight per day, such as 3 to about 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.